Predictors of outcome in adult patients with Relapsed/Refractory T-cell acute lymphoblastic leukemia

Abstract

Abstract Background: The outcome of adult patients with relapsed/refractory (R/R) T-cell acute lymphoblastic leukemia (T-ALL) remains poor with limited available treatment strategies. Novel treatment options are needed to improve response and survival in these patients. Methods: We conducted a retrospective analysis of adult patients (pts) with R/R T-ALL who received first salvage therapy (S1) at our institution from 1989–2024. Baseline clinical and disease characteristics, treatment history, and outcomes were collected. The primary objectives were to define predictors of response and overall survival (OS) from start of S1. Multivariate Cox regression was used to assess prognostic factors for response and OS, including age, immunophenotype, cytogenetics, mutations, salvage regimen, and transplant status. Results: We identified 95 pts with R/R T-ALL; median age at diagnosis was 32 yrs (range, 18–76), and 69% were male. Baseline median WBC was 76.5 x 109/L (range, 5.2 – 539), bone marrow blast 78% (range, 0-98), peripheral blasts 20.5 x 109/L (range, 0-54). Immunophenotyping showed early T-cell precursor (ETP) in 55.8%, non-ETP in 41.6%, and near-ETP in 2.6%. Common mutations included NOTCH1 (50%), TET2 (45.7%), ASXL1 (34.3%), and RAS pathway mutations (24.4%); Complex cytogenetics and KMT2A rearrangements were seen in in 10% and 4%, respectively. Frontline (F/L) regimens included HCVAD (46%), nelarabine-based (34%), pediatric-inspired regimens (9%), and venetoclax (VEN)-based regimens (6%). Among pts with measurable residual disease (MRD) assessed by flow cytometry, 42% achieved MRD negativity in first remission (CR1). Median duration of CR1 was 9.1 months (range, 0.7–152); 81.2% relapsed within 18 months. 16 patients (17%) underwent allogeneic hematopoietic stem cell transplantation (SCT) in CR1; median CR1 to relapse interval was 11.6 months (range, 2.4–152). Among 81 pts who received S1, 29% received HCVAD-based regimens, 22% MOAD, 22% VEN-based, and 19% nelarabine-based regimens. Overall response rate (ORR) was 57%; CR in 38%, CRi in 12%, and PR in 3%. 23 pts (28%) proceeded to SCT after S1. On univariate analysis, nelarabine use in the F/L setting was associated with higher odds of CR in S1 (OR 5.49; 95% CI 1.39–36.7; p=0.03), while complex cytogenetics (OR 0.16; 95% CI 0.03–0.70; p=0.01) was associated with lower odds of response. Age, WBC, immunophenotype, and SCT history were not significantly associated with response in S1. In multivariate analysis, no predictors were identified. Median OS following S1 was 8.1 months (range, 0.2–216), with 1-year and 2-year OS rates of 29% and 14%, respectively. Pts who underwent SCT had a significantly longer OS compared with those who did not (15.2 vs. 6.15 months, p < 0.01). On univariate analysis, older age (HR 1.019; 95% CI: 1.002–1.036; p = 0.03) was associated with worse OS, while achieving CR in S1 (HR 0.29; 95% CI: 0.15–0.53; p < 0.001) was associated with improved OS. Nelarabine use (HR 0.47; 95% CI: 0.21–1.04; p = 0.06) and PEG-asparaginase (HR 0.42; 95% CI: 0.15–1.16; p = 0.09) showed trends toward improved survival, while ETP phenotype, complex cytogenetics, and venetoclax use were not significantly associated with OS. On multivariate analysis, SCT (HR 0.26; 95% CI: 0.10–0.71; p = 0.009), nelarabine use (HR 0.26; 95% CI: 0.09–0.77; p = 0.01), and achieving CR in S1 (HR 0.20; 95% CI: 0.085–0.46; p < 0.001) remained independent predictors of improved OS. In ETP-ALL pts, nelarabine use (HR 0.25; 95% CI: 0.07–0.85; p = 0.03), venetoclax use (HR 0.18; 95% CI: 0.04–0.78; p = 0.02), achieving CR in S1 (HR 0.31; 95% CI: 0.13–0.75; p = 0.01) and SCT (HR 0.34; 95% CI: 0.13–0.85; p = 0.02) were significantly associated with improved OS. PEG-asparaginase use trended toward benefit (HR 0.16; 95% CI: 0.02–1.15; p = 0.07). In multivariate analysis, only nelarabine use (HR 0.09; 95% CI: 0.01–0.53; p = 0.008) and achieving CR in S1 (HR 0.15; 95% CI: 0.04–0.68; p = 0.01) remained independently associated with OS. Conclusions: R/R T-ALL carried poor prognosis, with a median OS of 8.1 months and 2-year OS of only 14%. Achieving CR in S1, undergoing SCT, and use of nelarabine were independently associated with improved survival. In the ETP-ALL subset, nelarabine use and achieving CR remained significant in multivariate analysis. These findings underscore the need for novel strategies to improve depth of response and long-term outcomes in this high-risk population.